Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking Iloperidone or Olanzapine or Placebo

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01920802
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 31
• Location: 1
• Arms: 3
• Duration (Months): 22
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this pilot randomized clinical trial is to begin to delineate the pathophysiological changes associated with antipsychotic associated metabolic side effects. The study will be performed in 36 healthy people between the ages of 18 and 30, who have never taken an antipsychotic, will undergo baseline laboratory tests before being randomized to 5mg BID of olanzapine or 6mg BID of iloperidone or placebo to take for up to 4 weeks. The primary outcome measure will be a correlation of early changes in leptin with weight gain. We will also record changes in food intake, resting metabolic rate, oral glucose tolerance and fasting insulin and glucose levels, lipids and inflammation markers. Subjects will be followed closely to monitor for safety throughout the 4-week study and will be discontinued if there is a medically significant change in metabolic status or other antipsychotic side effects. Metabolic assessments will be performed again at the time of discontinuation or at the end of an 4-week period, and change from baseline in the two treatment groups will be compared.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: olanzapine; Drug: iloperidone; Drug: Placebo	Phase 4

Detailed Description

Study hypotheses:

1. Early changes (baseline vs day 3) in leptin will correlate with later changes in weight (at study termination.)

2. Olanzapine will cause the greatest increase in calorie consumption from baseline on the multi-item meal compared with iloperidone or placebo.

3. Olanzapine subjects will report the greatest frequency/quantity of eating in food diaries, and report increased preference for calorically dense foods (ie, higher fat content) compared to iloperidone or placebo.

4. Early markers of endocrine changes caused by olanzapine will be greater than those caused by iloperidone or placebo, and these early changes will correlate with weight gain.

5. Olanzapine will have greater effects on glucose homeostasis than iloperidone or placebo, and these effects will be separate from effects on body weight and composition.

6. Early signs of metabolic disturbance, including glucose intolerance (greater excursion on OGTT) and insulin resistance (higher plasma insulin) will precede any significant weight gain.

7. Early evidence of glucose intolerance and/or insulin resistance will predict greater metabolic derangements with further dosing of olanzapine, as evidenced by exacerbated glucose intolerance on OGTT or higher plasma glucose/insulin levels. These effects may not necessarily parallel weight gain.

8. Olanzapine will be associated with greater markers of inflammation than iloperidone or placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Quantitative Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking the Antipsychotic Medications Fanapt (Iloperidone) or Zyprexa (Olanzapine) or Placebo
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: olanzapine 5mg BID olanzapine for up to 4 weeks	Drug: olanzapine; 5mg BID up to 4 weeks; Other Names: Zyprexa
Experimental: iloperidone 6mg BID iloperidone up to 4 weeks	Drug: iloperidone; 6 mg BID up to 4 weeks; Other Names: Fanapt
Placebo Comparator: placebo BID placebo up to 4 weeks	Drug: Placebo; BID up to 4 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Body Weight [baseline and 6 week visit]

   Delineate a pathophysiological mechanism of antipsychotic induced weight gain

2. Change in Adiposity [Baseline to Day 28]

   Total fat mass (excluding head) from baseline to Day 28

Secondary Outcome Measures

1. Change in Leptin [change in baseline to Day 3]

   Leptin levels measured at Day 3 compared to baseline

Other Outcome Measures

1. Change Glucose in People Taking Olanzapine or Iloperidone [Baseline to study termination (about 12 weeks)]

   To quantify, prospectively, change in glucose from baseline to Day 28

2. Change in Insulin [Baseline to Day 28]

   Change in Insulin levels from baseline to Day 28

3. Insulin Resistance [Baseline to Day 28]

   Homeostatic model assessment for Insulin Resistance (HOMA-IR) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin.

4. Change in Food Intake [Baseline to Day 28]

   Total grams of food consumed

5. Change in Lipid Metabolism [Baseline to Day 28]

   Change in lipid metabolism as measured by cholesterol/HDL ratio

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female between the ages of 18-35 with no history of any Axis-I diagnosis

• Does not meet criteria for substance abuse or dependence in the past six months

• Female subjects will use barrier-method, non-hormonal contraception

• Capacity to understand all the relevant risks and potential benefits of the study (informed consent)

• Must be able to speak and read English

Exclusion Criteria:

• Current or past Axis I psychiatric diagnosis, including alcohol or substance abuse or dependence (except nicotine or caffeine), but not including minor Axis I disorders (e.g. simple phobia)

• Lifetime use of psychotropic medications, including antipsychotics, antidepressants, mood stabilizers, and anxiolytics

• Presence or history of medical or neurological illness that, in the judgment of the investigator, could influence the results of the study

• Diagnosis of diabetes, hemoglobin A1C > 6.5, hypertension, or dyslipidemias, or elevated random or fasting glucose, abnormal lipid levels, BP 130/85

• BMI 25 or < 19, history of BMI >35, and/or waist circumference >35 inches for females, 40 inches for males

• Subjects who are pregnant or breast-feeding or planning to become pregnant during the study

• Acute suicidality

• Meets criteria for a Diagnostic and Statistical Manual, Version 4 (DSM-IV) defined eating disorder

• Use of, or clinical indication for, one or more of the following medications: lithium, anti-epileptic medication, steroids (oral or inhaled), stimulants, serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants, thyroid supplementation, sibutramine, metformin, thiazolidinediones, beta-blockers, clonidine, niacin

• Subjects who have had >10% change in their body weight within the three months prior to enrollment

• HIV positive subjects

• Presence of mental retardation or pervasive developmental disorder

• History of recent (within 6 months) significant self-injurious behavior or violence

• Daily multivitamin or B-complex vitamin use

• A known history of dieting and difficulty with weight loss

• A strong family history of diabetes and/or heart disease

• History of congenital long QT syndrome or prolonged corrected QT interval (QTc) on screening EKG (>450ms)

• Concomitant use of any medication that inhibits 2D6 or 3A4 metabolism

• Low serum potassium or magnesium

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Jeffrey Lieberman, MD, New York State Psychiatric Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01920802
• Other Study ID Numbers: 6525
• First Posted: Aug 12, 2013
• Last Update Posted: Mar 20, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Olanzapine; Iloperidone

Study Results

Participant Flow

Pre-assignment Detail	There were a total of 69 consents in the study, 31 of which were randomized (started study medication). 24 subjects completed the study. The baseline characteristics reported were for the 24 subjects who completed the study.

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Period Title: Overall Study
STARTED	11	9	11
COMPLETED	7	7	10
NOT COMPLETED	4	2	1

Baseline Characteristics

Arm/Group Title	Olanzapine	Iloperidone	Placebo	Total
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks	Total of all reporting groups
Overall Participants	7	7	10	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	7 100%	10 100%	24 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 28.6%	3 42.9%	1 10%	6 25%
Male	5 71.4%	4 57.1%	9 90%	18 75%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 10%	1 4.2%
Asian	1 14.3%	0 0%	0 0%	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	5 71.4%	5 71.4%	4 40%	14 58.3%
White	1 14.3%	1 14.3%	4 40%	6 25%
More than one race	0 0%	1 14.3%	0 0%	1 4.2%
Unknown or Not Reported	0 0%	0 0%	1 10%	1 4.2%
Region of Enrollment (participants) [Number]
United States	7 100%	7 100%	10 100%	24 100%
Starting BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.7 (0.3)	23.6 (0.6)	22.7 (0.5)	23.0 (0.5)
Education (years) (years) [Mean (Full Range) ]
Mean (Full Range) [years]	16.4	13.6	14.9	15

Outcome Measures

1. Primary Outcome

Title	Change in Body Weight
Description	Delineate a pathophysiological mechanism of antipsychotic induced weight gain
Time Frame	baseline and 6 week visit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Mean (Standard Deviation) [kg]	3.2 (1.0)	0.8 (0.7)	0.4 (0.5)

2. Primary Outcome

Title	Change in Adiposity
Description	Total fat mass (excluding head) from baseline to Day 28
Time Frame	Baseline to Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	11942 (3635)	14741 (7349)	11690 (5469)
Day 28	13312 (4246)	16366 (6857)	12081 (4649)

3. Secondary Outcome

Title	Change in Leptin
Description	Leptin levels measured at Day 3 compared to baseline
Time Frame	change in baseline to Day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Mean (Standard Deviation) [ng/dL]	2.47 (1.17)	1.76 (0.8)	1.16 (1.15)

4. Other Pre-specified Outcome

Title	Change Glucose in People Taking Olanzapine or Iloperidone
Description	To quantify, prospectively, change in glucose from baseline to Day 28
Time Frame	Baseline to study termination (about 12 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	11500.71 (2721.448)	14430 (2148.776)	10925.5 (1134.236)
Day 28	11276.43 (1231.773)	13975 (3813.754)	12179.5 (1252.944)

5. Other Pre-specified Outcome

Title	Change in Insulin
Description	Change in Insulin levels from baseline to Day 28
Time Frame	Baseline to Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	9.7749 (3.42727)	9.9316 (2.29266)	10.9619 (2.66812)
Day 28	12.0862 (7.39234)	10.873 (5.9051)	10.785 (2.62637)

6. Other Pre-specified Outcome

Title	Insulin Resistance
Description	Homeostatic model assessment for Insulin Resistance (HOMA-IR) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin.
Time Frame	Baseline to Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	2.0477 (0.70188)	2.0661 (0.56517)	2.2988 (0.52346)
Day 28	2.6147 (1.78901)	2.4733 (1.60855)	2.3362 (0.68093)

7. Other Pre-specified Outcome

Title	Change in Food Intake
Description	Total grams of food consumed
Time Frame	Baseline to Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	1101.7715 (288.60787)	1196.6557 (527.22574)	1567.526 (608.53519)
Day 28	1198.4071 (303.15123)	1154.1286 (686.19597)	1458.108 (731.06392)

8. Other Pre-specified Outcome

Title	Change in Lipid Metabolism
Description	Change in lipid metabolism as measured by cholesterol/HDL ratio
Time Frame	Baseline to Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine	Iloperidone	Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks	6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks	BID placebo up to 4 weeks Placebo: BID up to 4 weeks
Measure Participants	7	7	10
Baseline	2.71 (0.756)	2.57 (0.787)	2.7 (0.483)
Day 28	3.14 (1.069)	2.57 (0.787)	2.5 (0.527)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Olanzapine		Iloperidone		Placebo
Arm/Group Description	5mg BID olanzapine for up to 4 weeks olanzapine: 5mg BID up to 4 weeks		6mg BID iloperidone up to 4 weeks iloperidone: 6 mg BID up to 4 weeks		BID placebo up to 4 weeks Placebo: BID up to 4 weeks
All Cause Mortality
	Olanzapine		Iloperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Olanzapine		Iloperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Olanzapine		Iloperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		6/7 (85.7%)		2/10 (20%)
General disorders
Drowsiness	6/7 (85.7%)	6	6/7 (85.7%)	6	2/10 (20%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.